High storage stability inhalable compositions

ABSTRACT

Inhalable pharmaceutical compositions are provided, for use in the treatment of respiratory disorders such as asthma, rhinitis and chronic obstructive pulmonary disease (COPD). These compositions have high storage stability, and include formoterol and a corticosteroid.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a national phase application under 35 U.S.C.Section 371 filed from International Patent Application PCT/SE01/01118,filed 17 May 2001, which claims priority to United Kingdom patentapplication Ser. No. 0012260.6, filed 19 May 2000. The contents of theseapplications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a stable powder formulation comprisingformoterol or enantiomers of formoterol, a glucocorticosteroid and acarrier or diluent for use in the treatment of inflammatoryconditions/disorders, especially respiratory diseases such as asthma,COPD and rhinitis.

BACKGROUND OF THE INVENTION

Stability is one of the most important factors which determines whethera compound or a mixture of compounds can be developed into atherapeutically useful pharmaceutical product. When mixing differentingredients in a pharmaceutical formulation there exists the possibilityof interactions taking place between the components. In addition, eachcomponent may have different degradation characteristics.

Formoterol is a highly potent and selective β2-agonist with a longduration of action when inhaled. Compared to other β-adrenergiccompounds it has a unique chemical structure with a formamido groupsubstituted on the benzene ring. It has two asymmetric carbon atoms inthe molecule making four stereoisomers possible. Most studies, clinicaland preclinical, appear to have been performed with the fumarate (asdihydrate) of the enantiomeric mixture designed R;R+S;S. The R;Renantiomer is the most potent of the four enantiomers.

The stability profile of the drug formoterol (mainly as fumaratedihydrate) has been evaluated by investigating the influence ofvariables such as storage time, temperature, relative humidity, lightand pH on the content of formoterol and determining the amount ofchromatographic impurities. Formoterol (as fumarate dihydrate) has beendemonstrated to be stable under long-term storage even at hightemperatures and high relative humidities.

However, the chemical structure of formoterol makes the molecule proneto chemical degradation when in contact with e.g. a reactive specieslike an aldehyde or under stress conditions e.g. a milling process.

Potent drugs for administration by inhalation are generally formulatedin association with carriers/diluents such as lactose to facilitateaccurate dosing from an inhaler. These formulations have generallyconsisted of coarse particles of a carrier together with fine particlesof the drug(s), optionally together with small particles ofcarrier/diluent, which combination is generally known as an orderedmixture. An alternative to such a formulation is to agglomerate thesmall particles of the drug(s) and the carrier/diluent to agglomerates.

Formoterol (as fumarate dihydrate) as well as a carbohydrate such aslactose (preferably as the monohydrate) are very stable compoundsindividually, but degradation products are formed when the two compoundsare mixed. A mixture of formoterol fumarate dihydrate and lactosemonohydrate can be regarded as a three component system composed offormoterol fumarate, lactose and water. By sorption of water a saturatedaqueous lactose solution is formed at the surface of the powder mixture.A certain amount of formoterol fumarate dissolves in this aqueoussolution and is thereby susceptible to degradation. Therefore, therelative humidity, as well as the storage temperature, will influencethe stability of the powder mixture.

When adding a third ingredient in the mixture the formation ofdegradation products would be expected to be higher due to thecomplexity and the possibility for many degradation processes. It wouldtherefore be desirable to develop a formulation with good stability inspite of the complex mixture of compounds having reactive chemicalfunctions such as an amine (formoterol), formamide (formoterol),carbohydrate (e.g. lactose) and a keto function (glucocorticosteroid).The presence of hydrates (formoterol fumarate dihydrate, lactosemonohydrate) will make it even more complex.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting stability data for various inhalablecompositions stored in open dishes.

FIG. 2 is a graph depicting stability date for various inhalablecompositions stored in dry powder inhalers.

FIG. 3 is a schematic representation of the manufacturing process of thepresent invention.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided apharmaceutical composition in the solid state comprising, in admixture,a first active ingredient which is micronised formoterol or anenantiomer thereof, a second active ingredient which is a micronisedglucocorticosteroid and a carrier or diluent, the composition having ahigh storage stability.

By the term “high storage stability” is meant that the decomposition offormoterol in the formulation will be less than 10% when-stored in opendishes at 40° C. and 75% relative humidity for 6 months when the contentof formoterol is less than about 1.0% (w/w), preferably less than 0.8%(w/w) and most preferably less than about 0.6% (w/w) in the formulationor, when stored in a dry powder device, a decomposition of less thanabout 2.5% under the same conditions.

The formulations having the desired stability are prepared using a novelprocess which involves:

-   1. preparing a mixture of micronised first active ingredient and    micronised carrier/diluent-   2. optionally adding further micronised carrier/diluent to the    mixture-   3. addition and mixing of pre-micronised hydrophobic second active    ingredient, the second active ingredient being optionally pre-mixed    with micronised carrier/diluent, and-   4. either subjecting the mixture to agglomeration and    spheronisation, or adding coarse carrier/diluent.

The first active ingredient and carrier/diluent can be preparedaccording to step 1 by micronising the two components together or eachcan be micronised individually and then combined to give a micronisedmixture. Preferably the two components are mixed together and thenmicronised.

Preferably at step 3 the pre-micronised hydrophobic second activeingredient is added alone, ie in the absence of further micronisedcarrier/diluent.

Preferably step 4 involves subjecting the mixture to agglomeration andspheronisation.

By “micronised” is meant milling to give the a desired particle size orobtaining a desired particle size by any other means for producing smallparticles such as direct precipitation.

Optionally the mixture/ingredients can be conditioned at any suitablestage of the process, such as between steps 1 and 2, and/or the furtherpre-micronised carrier/diluent can be conditioned prior to addition atstep 2, and/or the further pre-micronised carrier/diluent can beconditioned prior to addition at step 3, and/or the mixture can beconditioned between the agglomeration and spheronisation in step 4.

Conditioning can be carried out according to the procedures described inWO 95/05805 or by selecting the process parameters such as relativehumidity in such a way that the final product when submitted to watervapour gives off heat of less than 1.2 joules per gram for the particleshaving a mean particle size of less than 10 μm as described and measuredin U.S. Pat. No. 5,874,063.

The invention therefore provides a pharmaceutical formulation in thesolid state comprising, in admixture, a first active ingredient which ismicronised formoterol or an enantiomer thereof, a second activeingredient which is a micronised glucocorticosteroid and acarrier/diluent and having a high storage stability characterised inthat the formulation is prepared by micronisation of the first activeingredient and carrier/diluent, optionally followed by mixingpre-micronised coarser carrier/diluent, mixing with micronisedhydrophobic second active ingredient, and finally either subjecting themixture to agglomeration and spheronisation or adding coarsecarrier/diluent.

The formoterol can be in the form of a mixture of enantiomers.Preferably the formoterol is in the form of a single enantiomer,preferably the R;R enantiomer. The formoterol can be in the form of thefree base, salt or solvate, or a solvate of a salt, preferably theformoterol is in the form of its fumarate dihydrate salt. Other suitablephysiologically salts include chloride, bromide, sulphate, phosphate,maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate,benzenesulphonate, ascorbate, acetate, succinate, lactate, glutarate,gluconate, tricaballate, hydroxynapaphthalenecarboxylate or oleate.

Preferably the second active ingredient is a micronisedglucocorticosteroid such as budesonide, fluticasone propionate,mometasone furoate, ciclesonide and epimers, esters, salts and solvatesof these compounds. More preferably the second active ingredient isbudesonide or an epimer thereof, most preferably the 22R-epimer ofbudesonide.

Preferably the carrier is a carbohydrate having a high storagestability, preferably a reducing carbohydrate such as lactose, glucose,galactose, mannose, xylose, maltose, cellobiose, mellibiose, maltotriose(e.g. as monohydrate). More preferably the carrier is lactose.

As used herein the term micronised carrier/diluent refers tocarrier/diluent having a mean particle size of less than about 25 μm,preferably less than about 10 μm, more preferable less than about 5 μm.The micronised carrier can be produced using processes known in the artsuch as micronisation or direct precipitation. The term coarsecarrier/diluent refers to carrier/diluent having a mean particle size ofgreater than about 25 μm.

As used herein the term micronised first active ingredient or micronisedsecond active ingredient means active ingredient having a mean particlesize of less than about 10 μm, preferably less than about 5 μm.

The pharmaceutical compositions according to the invention can be usedfor the treatment or prophylaxis of a respiratory disorder, inparticular the treatment or prophylaxis of asthma, rhinitis or COPD.

In a further aspect the invention provides a method of treating arespiratory disorder, in particular asthma, rhinitis or COPD, in amammal which comprises administering to a patient a pharmaceuticalcomposition as herein defined.

The compositions of the invention can be inhaled from a nebulizer, froma pressurized metered dose inhaler or as a dry powder from a dry powderinhaler e.g. multidose reservoir systems from AstraZeneca (Turbuhaler®)or Schering-Plough or from a dry powder inhaler utilizing gelatine,plastic or other capsules, cartridges or blister packs. Doses will bedependent on the severity of the disease and the type of patient.

The process of the invention is shown schematically in FIG. 3.

EXPERIMENTAL SECTION

The invention is illustrated by the following examples which are notintended to limit the scope of the application. In the examplesmicronisation is carried out such that the particle size range for eachof the active components is suitable for administration by inhalation.The determination of the formoterol degradation products was performedby reversed phase liquid chromatography, on a two column system usingLiChrospher 60 RP-select B. 5 μm particles with octylsilane asstationary phase. UV-detector at 214 nm. Evaluation was done as area-%since the degradation products were not fully known.

EXAMPLE 1

The following example is a reference example in which the formulation isprepared in a conventional manner.

Formoterol fumarate dihydrate (26 g) and lactose monohydrate (4.974 kg)are mixed for one or two hours in a tumbling mixer. This mixture wasmicronised in a spiral jet mill in order to attain a particle sizesuitable for inhalation. Micronisation of substances into the low micronrange (1-5 μm) may induce disturbances in the crystallinity of thesubstance. Amorphous areas are introduced, especially at the surfaces ofthe micronised substance. This morphological change of the substanceswill increase the sensitivity to humidity and thereby being an potentialimplement to stability problems. The crystal structure of the substancemixture was restored in a controlled way according to U.S. Pat. Nos.5,874,063 or 5,709,884.

To improve the flowability of the cohesive powder it was spheronised toagglomerates at room temperature at a controlled relative humidity ofless than 50%.

Stability data of a formoterol fumarate dihydrate (5 mg/g)/lactosemonohydrate (995 mg/g) micronised mixture and stored in open dishes at40° C. and 75% relative humidity for 6 months. Results see FIG. 1(A).

EXAMPLE 2

The following example is a reference example in which the formulation isprepared in a conventional manner.

The micronised and spheronised formoterol fumarate dihydrate/lactosemonohydrate formulation according to example 1 was filled in the powderdevice Turbuhaler® (AstraZeneca) and stored for 6 months at 40° C. and75% relative humidity. Results see FIG. 2(A).

EXAMPLE 3

Formoterol fumarate dihydrate (0.2 kg) and lactose monohydrate (34 kg)are mixed for one or two hours in a tumbling mixer. This mixture wasmicronised in a spiral jet mill in order to attain a particle sizesuitable for inhalation. The crystal structure was restored in acontrolled way according to U.S. Pat. Nos. 5,874,063 or 5,709,884. Thisconditioned product is mixed with micronised budesonide (3 kg) forthirty to sixty minutes in a tumbling mixer. As a second mixing step thepowder was fed to a modified spiral jet mill, operating at a very lowmilling pressure and a high flow of nitrogen. This will break upagglomerates without causing a further size reduction of the particles(and thereby creating amorphous areas and as a consequence loss ofstability) while improving the homogeneous distribution of budesonide inthe powder.

To improve the flowability of the cohesive powder it was spheronised toagglomerates at room temperature at a controlled relative humidity ofless than 50%.

Stability data of a formoterol fumarate dihydrate (5 mg/g)/budesoni,de(90 mg/g)/lactose monohydrate (905 mg/g) micronised mixture and storedin open dishes at 40° C. and 75% relative humidity for 6 months. Resultssee FIG. 1(B).

EXAMPLE 4

The micronised and spheronised formoterol fumarate dihydrate (5mg/g)/budesonide (90 mg/g)/lactose monohydrate (905 mg/g) according toexample 3 was filled in the dry s powder device Turbuhaler®(AstraZeneca) and stored for 6 months at 40° C. and 75% relativehumidity. Results see FIG. 2(B).

1. A method of manufacturing a pharmaceutical composition that includes,in admixture, a first active ingredient which is micronised formoteroloptionally in the form of a salt or solvate of a salt, a second activeingredient which is micronised glucocorticosteroid, and apharmaceutically acceptable carner/diluent, the method comprising: (a)preparing a mixture of the first active ingredient and a first portionof the carrier/diluent, both being in micronized form; (b) adding thesecond active ingredient in pre-micronized form to the mixture of step(a) and mixing; and (c) subsequent to step (b), adding a second portionof the carrier/diluent, in coarse form, to form a composition that is anordered mixture.
 2. The method of claim 1, further comprising: (d)storing at least a portion of the composition at a temperature aboveambient temperature for at least one month; and (e) after step (d),testing the composition to determine the extent of decomposition offormoterol in the composition.
 3. The method of claim 2 wherein step (d)comprises storing the composition at a temperature of at least 40° C. 4.The method of claim 2 wherein step (d) further comprises storing thecomposition in at least 75% relative humidity.
 5. The method of claim 2wherein step (d) comprises storing the composition for at least 6months.
 6. The method of claim 2 wherein no micronization step isperformed subsequent to step (c).
 7. The method of claim 2 wherein theproportion of formoterol in the composition of (c) is less than 1.0%(w/w).